Before the discovery of the cannabinoid CB1 and CB2 receptors, the term cannabinoid (CB) was used to describe the biologically active components of cannabis sativa, the most abundant of which are delta-9-tetrahydrocannabinol (THC) and cannabidiol.

THC is a moderately potent partial agonist of the CB1 and CB2 receptors and is considered the “classical cannabinoid,” a term now used to refer to other analogues and derivatives that are structurally related to the tricyclic dibenzopyran THC core. The term “non-classical cannabinoid” refers to CB agonists structurally related to cannabidiol.
Pharmacological investigations have concentrated on selective CB receptor modulators of the pyrazole structural class, which include SR 141716A (the monohydrochloride salt of SR 141716) and SR 144528. SR 141716A was the first potent and selective CB1 receptor antagonist.

Pyrazole CB modulators are among the many different structural classes which have aided the development of CB pharmacology, have helped to determine the biological effects mediated by the CB receptors, will lead to further refinement of current compounds, and will be a source of new chemical classes in the future.
Certain compounds (including SR 141716, SR 144528 and the like) that were originally classified as selective antagonists are now considered to act as “inverse agonists” rather than pure antagonists. Inverse agonists have the ability to decrease the constitutive level of receptor activation in the absence of an agonist instead of only blocking the activation induced by agonist binding at the receptor. The constitutive activity of CB receptors has important implications since there is a level of continuous signaling by CB1 even in the absence of an agonist. For example, SR 141716A increases CB1 protein levels and sensitizes cells toward agonist action, thus indicating that inverse agonists may be another class of ligands used to modulate the endocannabinoid system and the downstream signaling pathways activated by cannabinoid receptors.
Advances in the synthesis of CB and cannabimimetic ligands have furthered the development of receptor pharmacology and provided evidence for the existence of additional CB receptor sub-types. However, there remains an ongoing need for the identification and development of small molecule CB1 or CB2 receptor modulators for the treatment of a variety of CB receptor modulated syndromes, disorders, and diseases.
All documents cited herein are incorporated by reference.